Effect of histaminergic H1- and H2-receptor antagonists on neurophysin release in response to nicotine from cigarette smoking in normal men.

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Effect of histaminergic H1- and H2-receptor antagonists on
neurophysin release in response to nicotine from cigarette
smoking in normal men
Nicotine, inhaled as cigarette smoke, stimulates
the secretion of vasopressin and neurophysin
(Husain etal., 1975; Legros et al., 1977; Pokracki
et al., 1981; Pullan et al., 1979). A nicotine
stimulated neurophysin (NSN), specific for vaso-
pressin, has been found in the plasma of normal
men (Robinson, 1975) and used to determine the
neurohypophyseal
secretion
(Robinson, 1977).
Recent data suggest that histamine interferes
with some action ofnicotine, such as the effect of
nicotine on pulmonary artery (Chiou et al.,
1976).
histamine controls posterior pituitary function;
however, it has been reported that the intra-
cerebroventricular injection of histamine in-
duces an antidiuretic effect in the cat (Bennet &
Pert, 1974). Furthermore, anatomical studies
have found the presence of histamine in many
cerebral areas, particularly in the supraoptic
nucleus and in the posterior lobe of the pituitary
(Taylor et al., 1972). The present study was
carried out in order to determine whether in
normal men a histaminergic pathway plays a role
in the control ofnicotine stimulated neurophysin
secretion. Therefore, since the effect of hista-
mine could be mediated through specific recep-
tors of two types HI and H2, which are both
present in neural tissue (Schwartz, 1978), we
evaluated the effect of a H1-(dexchlorphenira-
mine) (Garbarg et al., 1980) and a H2- (cime-
tidine) (Brimblecombe et al., 1975) receptor
antagonist on the release of neurophysin in res-
ponse to nicotine.
Eleven normal males (20-32 years) gave in-
formed consent to participate in this study. All
subjects had normal routine blood tests andwere
habitual smokers (5-12 cigarettes per day). Two
crossover studies were performed in random
orderwith an interval of7 days. Eachsubject had
abstained from smoking for at least 12-15 h
before the tests.
Tests were performed 2 h post-prandially at
14.30-15.00 h. All individuals were in recumbent
position and received drinking water ad libitum.
Two intravenous cannulae were placed in two
different antebrachial veins of seven subjects.
One cannula was kept patent by slow saline
(NaCl 0.9%) infusion and was used for blood
sampling; the other for the administration of the
H2-receptor antagonist cimetidine (Tagamet, SK
& F, Milan, Italy) or saline. Basal blood samples
were collected at 45, 30, 15 and 0 min before
of
vasopressin
It has not been established whether
smoking and cimetidine or saline administration.
The intravenous (i.v.) injection of 400 mg of
cimetidine as a bolus at time 0 was followed by
the constant infusion of400mg of the same drug
diluted in 100 ml of saline. In the control test
saline was given in an equivalent volume.
In the experiments, in which the effect of the
Hi-receptor
(Polaramin, Essex Italiana, Milan, Italy) was
studied, four different men were injected intra-
venously at time 0 with 10 mg with this drug or
with an equal volume of saline. An intravenous
cannula was inserted in an antecubital vein for
blood sampling and kept open by the slow infu-
sion of normal saline.
In both tests, subjects started to smoke two
nonfilter cigarettes at time 0. Smoking was com-
pleted within 15 min; blood was collected 10, 20,
30, 40, 50, 60 min after dexchlorpheniramine,
cimetidine or saline injection. Neurophysin
plasma concentrations were assayedwith a speci-
fic RIA (Robinson, 1975) in duplicate and in the
same assay.
Statistical analysis was performed using analy-
sis of variance and two tailed Student's paired
and unpaired t-tests, as appropriate. While cime-
tidine and cigarette smoking did notproduce any
side effect, dexchlorpheniramine induced sleep-
iness in all men.
Cigarette smoking caused a clear release of
neurophysin (Figure 1). Dexchlorpheniramine
and cimetidine did not modify the stimulatory
effect of smoking (Figure 1). In some subjects
(lower panel of the Figure 1) the mean peak (4.5
+ 1.2 ng/ml) was higher than in others (2.2 + 0.6
ng/ml) (upper panel ofthe Figure 1). The reason
for this difference is unknown; however, this
increased response was not statistically different.
These data fail to produce evidence that hista-
mine exerts an influence on neurophysin release
induced by nicotine. Even though dexchlor-
pheniramine and cimetidine were used in doses
known to block central HI- (Pontiroli et al.,
1981) and H2- (Burland et al., 1979) histaminer-
gic receptors, neurophysin release in response to
nicotine stimulation did not change. Therefore,
it is not likely that a histaminergic pathway is
involved in the control ofthe nicotine-stimulated
neurophysin secretion. This effect could result
from an activation ofsome other neurotransmit-
ter. Further experiments are needed to elucidate
the exact actionsofnicotine and histamine on the
secretion ofneurohypophyseal hormone in man.
antagonist
dexchlorpheniramine
Br. J. clin. Phartnac.(1984),18
Letters to the Editors
109

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110
Letters to the Editors
Br. J. clin. Pharnac. (1984), 18
3
Dexchlorpheniramine
Cd
10mg or saline
z
z
-45
-30-15
0
Time (min)
10
20
30
40
5060
Cimetidine 400 mg 60 min. or saline
Cimetidine 400 mg
1h 4
or saline
C.33
z
Z 2
1
-45 -30
-15
0
10 20 30 40 50 60
Time (min)
Figure 1
(
Values are given as mean ± s.e mean.
Upperpanel: statistical analysis was not performed considering the low number ofobservations; however
the NSN response to nicotine after dexchlorphenira mine is similar to that obtained in basal conditions.
Lowerpanel: a significant increase to NSN levels in response tocigarette smokingwas observedfrom 10 to
60min (P< 0.02 at30min; P< 0.025 at 10, 20, 40min; P < 0.05 at 50 and 60 min vs the 0 min value). Cime-
tidine did not modifyNSN response to cigarette smok ing.
Effect ofcigarette smoking on plasma neurophysin (NSN) levels under basal conditions
) and after i.v. administration of dexchlorpheniramine ( ---
-
) in male subjects.
We
NIAMDD, Bethesda, Md, USA, for the gifts of
materials used in the neurophysin RIA.
thank
the National
Pituitary Agency,
P. CHIODERA, G., ROSSI', L. CAMELLINI',
M.L. MAFFEI, R. VOLPI& V. COIRO
Istituto di Clinica Medica Generale e Terapia
Medica,
University of Parma,
Laboratorio
RIA,
Ospedale
Guastalla, Italy.
Parma and
Guastalla,
di
Received December 2, 1983,
accepted March 12, 1984
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Sources of support for the staff of academic departments of
clinical pharmacology in the United Kingdom
Financial restraints in the National Health Service
(NHS), universities and charitable foundations
are adversely affecting most academic clinical
disciplines. Clinical pharmacology has grown
rapidly in British universities during the past 15
years, but no formal studies have been con-
ducted into the sources of its financial support.
A survey of the financial support of the staff of
academic departments of clinical pharmacology
in the United Kingdom has, therefore, been
carried out.
Academic appointments in clinical pharma-
cology exist in all but one of the NHS Region.
The exception is the East Anglia Region, where
Cambridge University has a medical school but
no clinical pharmacology department. Twenty-
eight medical schools in the United Kingdom
have appointments in clinical pharmacology and,
in addition, there are two university departments
of clinical pharmacology which are not within
undergraduate medical schools (Bath and Royal
Postgraduate Medical School, London). Ques-
tionnaires were sent to the senior academic
representatives in clinical pharmacology in each
University school, asking them to indicate the
number ofstaffon 31 December 1983, according
to status and their support (Table 1).
They were also asked if their department is
independent of, or linked to the department of
basic pharmacology in their medical school.
Specialist units in the Institutes of Psychiatry
and of Dermatology, London, were excluded
from the survey, as alsowere non-academicNHS
departments such as that in Stoke-on-Trent.
In the analysis of results, it was decided for
convenience to express the results for Consultant/
Professor/Senior Lecturer as full-time equivalents
because of shared support by the NHS and Uni-
versities of several senior staff.
Replies were obtained from 30 university de-
partments. All except one were designated as
departments or units of clinical pharmacoldgy.
The exception was the University of Bristol
which has a joint appointment in clinical phar-
macology between the Departments ofMedicine
and Pharmacology but no designated unit. Of
the 27 departments in undergraduate medical
schools, 14 were independent of, and 13 were
linked with, their basic pharmacology depart-
ments.
Information on staffnumbers and their sources
of support is summarised in Table 1. 'Other'
sources of support include charitable foundations
other than the Medical Research Council (MRC)
and Wellcome Trust, visiting fellowships, and
salaries from foreign governments to their own
graduates training in this country. 'Other' staff
include non-clinical lecturers, visiting research
and training fellows who have not been given
honorary lecturer status, and technicians. This
category is almost certainly incomplete as some
departmental returns included only medically